This invention relates to miniaturized drug delivery devices and more particularly, to controlled time and rate release multi-welled drug delivery devices.
The efficacy of many drugs is directly related to the way in which they are administered. A wide variety of methods for controlled release have been developed, including pumps, patches, tablets, and implants. However, all of these methods have unique disadvantages when considering the treatment of a chronic condition. A major disadvantage of both external and internal micropumps is that they depend on the reliable operation of moving parts. Failure of the pump due to breakage, leakage, or clogging may be catastrophic for the individual. Patches are useful only for certain chemicals that may be absorbed through the skin. Tablets are widely used but can achieve release for only a limited amount of time before they pass through the digestive system. Many polymeric materials proposed to be used for pulsatile release of a chemical are responsive to changes in pH or temperature (Lee, et al., J. Appl. Polym. Sci., 62:301-11 (1996)), the application of ultrasound (Kost, et al., Proc. Nat. Acad. Sci., USA, 86:7663-66 (1989); Levy, et al., J. Clin. Invest., 83:2074-78 (1989)), changes in enzymes, or changes in electric (Kwon, et al., Nature, 354:291-93 (1991)) or magnetic (Kost, et al., J. Biomed. Mater. Res., 21:1367-73 (1987)) fields. These polymeric systems are limited to the release of only one or a few chemicals, and may need to be tailored to the specific condition which they are to treat (glucose-sensitive insulin release systems for the treatment of diabetes, for example (Kitano, et al., J. Control. Release, 19:162-70 (1992))). Additionally, the stimuli source may be large, expensive, or too complex for frequent use. Moreover, fabrication procedures for implants such as microspheres are usually complex, and the solvents or heat used during fabrication can adversely affect the stability of the drugs contained in the microspheres.
U.S. Pat. Nos. 5,797,898 and 6,123,861, to Santini, et al., describe active and passive microchips for drug delivery. However, the fabrication methods described therein are primarily based on standard microelectronics processing techniques. It would be advantageous to provide additional, preferably simple and inexpensive, methods of manufacturing such microchip devices. It would also be advantageous to develop new methods of triggering and controlling release of the molecules.
PCT WO 99/03684 discloses a process of making a device having a surface microstructure of wells or channels using a low cost process of screen printing a curable or polymerizable material onto a plastic substrate and then curing or polymerizing the material. The device can contain hundreds of wells and be used as a microtitre plate array, holding reagents of interest, but it is not designed to provide any sort of controlled release or delivery function.
It is therefore an object of the present invention to provide a variety of techniques for the manufacture, particularly the low cost manufacture, of multi-welled microchip devices for the controlled release of drugs and other molecules.
It is another object of the present invention to provide a device that allows delivery of drugs or other molecules in either a pulsatile or continuous manner, using a variety of materials of construction and methods for triggering and controlling release of the molecules.
Methods are provided for manufacturing microchip devices for the storage and controlled release of molecules, such as drugs. Methods include compression molding, injection molding, thermoforming, casting, and combinations of these techniques, alone or in combination with microfabrication techniques. The methods are adapted to make either active or passive release devices from materials such as polymers, ceramics, and metals. In a preferred embodiment, polymeric devices are made by (1) filling a die with a polymer powder; (2) compressing the powder to form a partially or completely dense polymer preform; (3) thermal compression molding the preform in a mold to form a substrate, wherein the mold has a plurality of protrusions which form reservoirs in the substrate; and (4) filling the reservoirs with a release system comprising the molecules to be released. Alternatively, ceramic devices are formed from a ceramic powder or a slurry thereof which is cast in a mold to form the substrate, again wherein the mold has a plurality of protrusions which form reservoirs in the substrate.
Each filled reservoir optionally can include reservoir caps that control release. In devices of any substrate material, methods of forming reservoir caps can utilize capillary action depending upon the selection of appropriate reservoir dimensions.
These fabrication methods preferably further include exposing (i.e. opening) the ends of the reservoirs after molding or casting, by cutting the substrate, planarizing the surface of the substrate, or a combination of these techniques.
The release system may be formed solely of the molecules to be released in pure form or the molecules may be combined with a release-controlling component, such as a polymeric matrix, which affects the release rate and time through degradation, dissolution, swelling, or disintegration of the component. The release system also may include a material that does not undergo such processes, but affects the molecule release rate via diffusion of the molecules through the material. In one embodiment of active release systems, the reservoirs are provided with a cap that covers the reservoir and responds directly to an applied external stimulus (e.g., an applied voltage or potential), or to a change in the local environment of the device or reservoir, which is brought about by the application of the external stimulus (e.g., local pH change or generation of an electric field due to the application of a voltage or potential to electrodes in or near the reservoir). In a preferred embodiment, active release devices are provided with electrodes positioned in, near, or partially covering the reservoirs, such that upon application of an electric potential or current across the electrodes, the release system (1) degrades due to local pH changes or (2) exchanges ions in solution with an ionically bound active substance, thereby releasing the molecules from the release system. For example, the release system can be a biodegradable matrix. In another embodiment, the electrodes drive charged molecules from the release system upon application of an electric current across the electrodes.